The present invention relates to a process for preparing carotenoid polyene chain compounds. More specifically, it relates to intermediate compounds which are useful for synthesis of carotenoid compounds having polyene chain structure, and a process for preparing the same, and a process for preparing polyene chain compounds, especially lycopene, by using the intermediate compound.
Carotenoid compounds have polyene chain structure. Specific examples of the compounds include beta-carotene, lycopene, astaxanthin, bixin, and the like. The carotenoid compounds have been widely used as natural dyes, and recently, these compounds are reported to have excellent anti-tumor effect, by virtue of their selective reactivity with radicals and singlet oxygen known as carcinogens. In these circumstances, a variety of commercial products containing carotene, including cosmetics or taste food, have been merchandised. However, there still remain conflict opinions on the anti-tumor activity of beta-carotene, since beta-carotene is reported to have a harmful effect on smokers or patients having lung cancer. Thus, people pay more increasing attention to lycopene, having stronger anti-oxidation ability with no conflict opinion on the anti-tumor activity.
To meet such a tendency, the requirement of developing a process for effectively synthesizing polyene chain structures that construct lycopene also increases.
In the meanwhile, the most representative conventional synthetic process for preparing lycopene was developed by Isler; that is a process for synthesizing polyene chain on the basis of Wittig reaction (Reaction Scheme 1; Helv. Chim. Acta 1956, 39, 463-473). 
According to Reaction Scheme 1, C-10 dialdehyde compound is subsequently reacted with vinyl ether and propenyl ether compound to form a continuously conjugated carbon chain wherein each C-2 unit and C-3 unit was respectively added to the aldehyde groups of C-10 dialdehyde compound. Throughout the stage, C-10 unit has been added to the dialdehyde to form C-20 dialdehyde, of which the triple bond at the center of the molecule was then partially reduced to give crocetin.
Then, crocetin thus obtained is subjected to Wittig Reaction with Wittig salts to form lycopene. The Wittig salts used in this stage is what was prepared as a result of reaction of geranyl bromide with triphenylphosphine.
However, the synthetic process for lycopene according to Reaction Scheme 1 includes many reaction stages to carry out in order to form crocetin, and the synthetic efficiency is low owing to the trouble in treating phosphine oxide as the by-product obtained as a result of Wittig Reaction.
Another synthetic process for synthesizing lycopene is developed by Karrer. The process is based on coupling reaction by using alkynyl anion, partial hydrogenation and dehydration. The synthetic process is illustrated in Reaction Scheme 2 (Helv. chim. Acta 1950, 33, 1349-1352). 
According to Reaction Scheme 2, an anion obtained by adding metallic zinc to propargylic bromide is subjected to coupling reaction with "psgr"-ionone, to give C-16 intermediate. Then, two molecules of the alkynyl anion obtained by adding bases to the C-16 intermediate were coupled with C-8 diketone compound to form forwards containing 40 carbon atoms required for synthesis of lycopene. The partial hydrogenation of the two triple bonds and dehydration of the forward compound provide lycopene.
The synthetic process for lycopene according to Reaction Scheme 2 is relatively simple, however, it is not easy to form a double bond having trans configuration.
Thus, the first technical object of the present invention is to provide an allylic sulfide, that is, a C-5 compound usable for chain extension to effectively synthesize polyene chain structure described above.
Another technical object of the present invention is to provide a process for extending the carbon chain by the use of said allylic sulfide.
Still another object of the present invention is to provide a process for preparing polyene chain compounds, especially lycopene, by using said process for extending carbon chain.
In order to achieve the first technical object, the present invention provides allylic sulfides represented by Chemical Formula 1:
Chemical Formula 1
Wherein, X is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2CH3, and Ph represents phenyl group.
The second technical object of the present invention is achieved by a process for preparing an allylic sulfide of Chemical Formula 1, which comprises the steps of (a-1) oxidizing isoprene to obtain isoprene monoxide, (b-1) reacting the isoprene monoxide with benzene thiol to obtain 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A); and (c-1) reacting the compound (A) with a halogenating compound or sulfonylating compound. 
In the formulas, X is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2CH3, and Ph represents phenyl group.
The third technical object of the present invention is achieved by a process for extending carbon chain by the use of allylic sulfide of Chemical Formula 1, which comprises the steps of (a-2) deprotonating allylic sulfone compound (B), and reacting the resultant compound with allylic sulfide of Chemical Formula 1 to obtain thio-sulfone compound (C); and (b-2) selectively oxidizing the thio-sulfone compound (C) to obtain the corresponding allylic sulfone compound (D). 
In the formulas, R is selected from the group consisting of hydrogen, C1xcx9cC30 alkyl group, C1xcx9cC30 alkenyl group, aryl group, xe2x80x94CN, xe2x80x94COORxe2x80x2 (wherein, Rxe2x80x2 is C1xcx9cC10 alkyl group) and xe2x80x94C(xe2x95x90O)H, X is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2 CH3, and Ph represents phenyl group.
The fourth technical object of the present invention is achieved by a process for preparing a carotenoid polyene chain compound represented by Chemical formula 2, which comprises the steps of (a-3) deprotonating the allylic disulfone compound (D), and reacting the resultant compound with not more than 0.5 equivalent of diallylic sulfide (E) (wherein, Y is a halogen atom) on the basis of 1 equivalent of allylic disulfone compound (D) to obtain allylic sulfide compound (F); (b-3) selectively oxidizing the allylic sulfide compound (F) to obtain allylic sulfone compound (G); (c-3) subjecting the allylic sulfone compound (G) to Ramberg-Baklund reaction to give tetra(phenylsulfonyl)-triene compound (H); and (d-3) reacting the compound (H) with a base. If R of Chemical Formula 2 is prenyl, the process provides lycopene. 
In the formulas, R is selected from the group consisting of hydrogen, C1xcx9cC30 alkyl group, C1xcx9cC30 alkenyl group, aryl group, xe2x80x94CN, xe2x80x94COORxe2x80x2 (wherein, Rxe2x80x2 is C1xcx9cC10 alkyl group) and xe2x80x94C(xe2x95x90O)H, Y is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2CH3, and Ph represents phenyl group.
In the process for preparing an allylic sulfide of Chemical Formula 1, the ring opening of isoprene monoxide of stage (b-1) is preferably performed by using Cu(I)-containing salt as a catalyst, and N,N-dimethylformamide (DMF) as solvent, because the objective compound having a double bond of trans configuration can be obtained as major product under such reaction conditions.
In the process for extending carbon chain by the use of allylic sulfide of Chemical Formula 1, specific examples of R include methyl, ethyl and propyl group for C1xcx9cC30 alkyl group, vinyl, allyl and prenyl group for C1xcx9cC30 alkenyl group, and phenyl and naphthyl group for aryl group. X is preferably Cl or Br in terms of reactivity, while R is preferably hydrogen or prenyl.
Further, the C-5 unit can be added as desired by repeating stage (a-2) and (b-2) one or more times by using compound (D) as the starting material.
Selective oxidation of stage (b-2) can be preferably performed by adding hydrogen peroxide solution dropwise to thio-sulfone compound (C) in the presence of a metal oxide catalyst such as lithium molybdenate-niobate (LiNbMoO6) or vanadium oxide (V2O5) at room temperature. Selective oxidation under such reaction conditions gives excellent yields.
In the process for preparing a carotenoid polyene chain compound represented by Chemical formula 2, specific examples of R include methyl, ethyl and propyl group for C1xcx9cC30 alkyl group, vinyl, allyl and prenyl group for C1xcx9cC30 alkenyl group, and phenyl and naphthyl group for aryl group. In particular, it is preferable that R is hydrogen or prenyl.
In the stage (a-3), Y of compound (E) is preferably Br in terms of reactivity, if R of allylic disulfone compound (D) is hydrogen or prenyl. Deprotonation of allylic disulfone compound (D) should be performed by adding 2 equivalent of base to 1 equivalent of allylic disulfone compound (D) at low temperature, preferably at a temperature not higher than xe2x88x9240xc2x0 C. Specific examples of the base include n-BuLi, s-BuLi, t-BuLi, phenyl lithium, NaNH2, lithium diisopropylamide (LDA), lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like.
Selective oxidation of stage (b-3) can be preferably performed by adding a mixture of urea-hydrogen peroxide (UHP) and phthalic anhydride dropwise to allylic disulfone compound (D) at low temperature, or adding hydrogen peroxide solution dropwise to sulfide compound (D) in the presence of a metal oxide catalyst such as lithium molybdenate-niobate (LiNbMoO6) or vanadium oxide (V2O5) at room temperature.
Ramberg-Baklund reaction of stage (c-3) is preferably carried out under a condition excluding oxygen in the air, for example, under nitrogen or argon atmosphere in terms of reactivity and yield.
The base used in stage (d-3) is not particularly restricted. Specific examples include NaNH2/NH3, and metal alkoxides such as CH3OK/CH3OH, CH3ONa/CH3OH, CH3CH2OK/CH3CH2OH, CH3CH2ONa/CH3CH2OH and t-BuOK/t-BuOH. Among them, metal alkoxide is more preferably used as the base.
The allylic sulfide of Chemical Formula 1 according to the present invention, which can be used as a ground material for chain extension due to the bonding with allylic sulfone compound in the course of synthesizing a polyene chain containing compound, is synthesized as described below:
Firstly, isoprene is oxidized to give isoprene monoxide. Though the oxidation reaction may be carried out under a conventional oxidative reaction condition, the present invention employs the condition of using an oxidant such as m-chloroperoxybenzoic acid (MCPBA), or of forming a corresponding halohydrin from isoprene (J. Am. Chem. Soc., 1950, 72, 4608-4613) which is then reacted with a base. Among them, the latter is more preferable as considering regio-selectivity of the two double bonds of isoprene on the electrophilic reactant.
Then, the isoprene monoxide is reacted with benzene thiol (PhSH) to provide 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A). In the reaction, it is preferable to employ Cu(I)-containing salt as a catalyst, and N,N-dimethylformamide as solvent in the aspect of reactivity and yield. Under these reaction conditions, the reactivity is high so that the reaction can be performed under mild condition at ambient temperature, and the reaction process itself is simple and easy to provide economic and practical advantages. The yield is also good. As the Cu(I)-containing salt, any salt having Cu+ ion is usable, but CuCN, CuBr, CuI or CuCl is preferably used. The Cu(I)-containing salt is used in a catalytic amount, more specifically, 0.001xcx9c0.1 mol % of the salt is preferably used on the basis of 1 mole of isoprene monoxide.
As a result of the above reaction, ring opening at the allylic position of the epoxide compound is performed. In the 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) molecules thus obtained, trans configuration prevails in a trans:cis ratio of 6:1 or more.
Thereafter, 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) is subjected to halogenation or sulfonylation to provide allylic sulfide of Chemical Formula 1. In this stage, halogenation of 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) may be carried out under various reaction conditions. For example, halogenation can be performed by employing a reaction condition of CH3SO2Cl/LiCl, SOCl2, (COCl)2, PPh3/CCl4, HCl, PBr3, PPh3/NBS or HBr. Sulfonylation may be carried out under various conditions as well, for example under the condition of using a sulfonyl compound such as CF3SO2Cl, PhSO2Cl, CH3C6H4SO2Cl and CH3SO2Cl with a base such as triethylamine (Et3N) and pyridine (Reaction Scheme 3). 
In the formulas, X is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2CH3, preferably from xe2x80x94Cl and xe2x80x94Br.
Now, the reaction of ring opening at the allylic position of the isoprene monoxide is described in detail.
The ring opening reaction of isoprene monoxide may be carried out under the conditions other than the reaction condition used in the present invention. Specific reaction conditions and the product distribution under each condition are shown in Table 1 below. In Table 1, Entry 5 corresponds to the reaction by using Cu(I)-containing salt and benzenethiol according to the present invention, while Entries 1 to 3 to the reaction of isoprene monoxide under basic condition, and Entries 4 and 6 to the reaction under acidic condition. The ratios of cis:trans double bond in 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) are determined by using gas chromatography and 1H-NMR.
As shown in Table 1, in case of Entries 1 to 3, compound (I) was obtained as the main product, while the desired 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) was not produced at all, or was produced in an extremely small amount. In case of Entry 4, 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) was synthesized at a low yield of about 22%, and the cis:trans ratio showed relatively low trans product (1:4) as compared to Entry 5.
In case of Entry 6 (Tetrahedron Lett. 1981, 22, 2413-2416), the desired compound, 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) could be obtained at a high yield of 93%, however, only to provide cis-configuration of compound (A). In case of Entries 7 and 8, 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) of which trans configuration prevails could be obtained, however, the synthetic yield of 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) was very low (3% and 7%, respectively).
On the contrary, in case of Entry 5, the reaction condition of the present invention, 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) was obtained with an excellent yield of about 87%, and the trans configuration prevails with cis:trans ratio of 1:6 or less. As shown above, 4-hydroxy-3-methyl-2-butenyl phenyl sulfide (A) of which trans configuration of double bond prevails could be synthesized at a high yield under the reaction condition according to the present invention.
In the meanwhile, in order to synthesize the carotenoid polyene chain compounds of Chemical Formula 2, which is represented by lycopene, the allylic sulfone compound (D) having extended carbon chain as desired should be firstly synthesized. As referring to Reaction Scheme 4, the process for preparing di(allylic sulfone) compound (D) is described here-in-below:
After deprotonation of the starting material, allylic sulfone compound (B), by treating with base, allylic sulfide of Chemical Formula 1 is added thereto, to obtain thio-sulfone compound (C) with 5-carbon chain extended. The specific examples of the allylic sulfone compound (B) include geranyl sulfone (R=prenyl) and prenyl sulfone (R=hydrogen). As the base, n-butyl lithium (n-BuLi) is preferably used.
The chain extension may be carried out at ambient temperature, but more preferably at a low temperature of 0xc2x0 C. or lower. In case of chain extension by using geranyl sulfone as the starting material, X of the compound of Chemical Formula 1 is preferably Br in terms of reactivity.
Then, the sulfide group of thio-sulfone compound (C) is selectively oxidized to provide the corresponding allylic disulfone compound (D). The selective oxidation is preferably carried out under the condition of employing metal oxide such as LiNbMoO6 or V2O5 as a catalyst, and hydrogen peroxide (H2O2) as an oxidant. 
In the formulas, R is selected from the group consisting of hydrogen, C1xcx9cC30 alkyl group, C1xcx9cC30 alkenyl group, aryl group, xe2x80x94CN, xe2x80x94COORxe2x80x2 (wherein, Rxe2x80x2 is C1xcx9cC10 alkyl group) and xe2x80x94C(xe2x95x90O)H, X is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2CH3.
When R is xe2x80x94CN, xe2x80x94COORxe2x80x2 (wherein, Rxe2x80x2 is C1C10 alkyl group) or xe2x80x94C(xe2x95x90O)H, the corresponding compound can be prepared according to conventional processes to introduce such a functional group.
If the process for chain extension is repeated, novel allylic sulfone compounds with increased five carbon numbers can be obtained every time.
Now, the synthesis of carotenoid polyene chain compound represented by Chemical Formula 2 according to the present invention is described in detail (see Reaction Scheme 5). The process for preparing carotenoid polyene chain compound according to the present invention is based on the process for synthesizing beta-carotene developed by the present inventors (J. Org. Chem. 1999, 64, 8051-8053). It is characterized by using di(haloallylic) sulfide (E) in order to synthesize C-10 triene structure of the center of the polyene chain, and applying Ramberg-Bxc3xa4klund reaction to diallylic sulfone obtained by oxidation of the sulfide compound.
In order to obtain the carbon skeletal required for carotenoids, di(haloallylic) sulfide (E) is combined with 2 equivalents or more of allylic disulfone compound (D) based on 1 equivalent of compound (E) by means of Julia method (Bull. Soc. Chim. Fr., 1973, 743-750), to obtain allylic sulfide (F). The coupling reaction of di(haloallylic) sulfide (E) with allylic disulfone compound (D) is preferably carried out by adding 2 equivalents of base such as n-BuLi to allylic disulfone compound (D) to deprotonate the compound, and then the reaction is performed under a temperature condition of xe2x88x9240xc2x0 C. or lower. In di(haloallylic) sulfide (E), Y is preferably Br in terms of reactivity.
Then, only the sulfur of allylic sulfide (F) is selectively oxidized to give the corresponding sulfone compound (G). The selective oxidation reaction is preferably carried out by adding a mixture of UHP and phthalic anhydride dropwise to allylic sulfide compound (F) at a low temperature, or by adding H2O2 dropwise to the compound in the presence of LiNbMoO6 or V2O5 as a catalyst at ambient temperature. Under such a reaction condition, only sulfur is selectively oxidized without oxidation of the double bond of allylic sulfide (F).
Thereafter, SO2 at the center of the structure of sulfone compound (G) is removed to form a double bond to provide compound (H). This reaction is preferably performed by treating sulfone compound (G) under Ramberg-Bxc3xa4klund reaction condition (J. Am. Chem. Soc., 1969, 91, 7510-7512).
Lastly, four benzenesulfonyl groups are removed from compound (H) by heating the compound in the presence of alcohol solvent and alkoxide base such as sodium alkoxide, to synthesize the polyene chain compound of Chemical Formula 2 represented by lycopene. 
In the formulas, R is selected from the group consisting of hydrogen, C1xcx9cC30 alkyl group, C1xcx9cC30 alkenyl group, aryl group, xe2x80x94CN, xe2x80x94COORxe2x80x2 (wherein, Rxe2x80x2 is C1xcx9cC10 alkyl group) and xe2x80x94C(xe2x95x90O)H, X is selected from the group consisting of xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OSO2CF3, xe2x80x94OSO2Ph, xe2x80x94OSO2C6H4CH3 and xe2x80x94OSO2CH3.
When the carotenoid compounds represented by lycopene are prepared according to the present invention (Example 1 to 10), the synthetic process is simpler, easier and more efficient than conventional processes. In addition, the problem of treating byproducts such as phosphine oxide can be prevented according to the present invention. The process of the present invention is also advantageous in easily forming the polyene chain structure having trans configuration of double bond.
Allylic sulfide compound of Chemical Formula 1 according to the present invention is very useful for an intermediate compound to extend C5 chain, during the course of synthesis of polyene chain compound such as lycopene.
According to the present invention, a carotenoid polyene chain compound represented by lycopene of Chemical Formula 2 can be prepared by coupling of allylic sulfone compound (D) of the desired chain length and di(haloallylic) sulfide compound (E), and oxidizing the sulfide to give the corresponding diallylic sulfone compound, which is then subjected to Ramberg-Bxc3xa4klund reaction, and finally eliminating the sulfonyl groups to give conjugated double bonds.
The invention is described in more detail by referring to the examples below, but it should be noticed that the present invention is not restricted to the examples by any means.